Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

Abstract

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45 immune cells and the percentage of active CD8 T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects

“…20 Epigenetic treatment induces a type I IFN response due to induction of endogenous retroviruses (ERVs). 9,10,15 We evaluated the expression of three ERVs ( ERV-3, MuMLV and Syncytin-a ) upon EMA treatment. Syncytin-a was significantly upregulated by the combination of DAC and Quis (Supplementary Figure S6A), while the other tested ERVs remained undetected (data not shown).…”

“…35 Recent pre-clinical work on the combination of the DNMTi azacytidine and several HDACi showed profound alterations in the tumor microenvironment in lung cancer and ovarian cancer. 9,10 Epigenetic treatment alone or in combination with PD-1 blockade of ovarian tumors resulted in significant more activated IFN γ-positive CD8-positive or CD4-positive T cells, and IFN-γ-positive NK cells in addition to significant less macrophages and myeloid-derived suppressor cells in the tumor microenvironment. 10 Likewise, in the lung cancer model, increased numbers of active IFN-γ- and CD8-positive T cells and reduced numbers of macrophages were identified.…”

“…9,10 Epigenetic treatment alone or in combination with PD-1 blockade of ovarian tumors resulted in significant more activated IFN γ-positive CD8-positive or CD4-positive T cells, and IFN-γ-positive NK cells in addition to significant less macrophages and myeloid-derived suppressor cells in the tumor microenvironment. 10 Likewise, in the lung cancer model, increased numbers of active IFN-γ- and CD8-positive T cells and reduced numbers of macrophages were identified. 9 While the total number of CD8-positive or CD4-positive T cells did not alter in these studies, we observed increased total numbers of naive and memory CD8-positive T cells and naive, memory and effector CD4-positive T cells based on CD44 and CD62L positivity.…”

“…8–10 In MM patients, combining lenalidomide and the DNMTi azacytidine stimulated an adaptive immune response by inducing the expression of antigens. 11 DNMTi and HDACi induced MAGE-A3 expression in primary MM cells, thereby stimulating recognition by MAGE-A3 cytotoxic T lymphocytes (CTLs).…”

“…15 Moreover, enhanced anti-tumor immunity by combining DNMTi with HDACi involves type I IFN, MYC depletion and profound alterations in the tumor microenvironment. 9,10 …”